|Year : 2016 | Volume
| Issue : 2 | Page : 57-62
Prevalence of hypothyroidism in common bile duct stone patients
Srinivas Sidduri1, Babulreddy Hanmayyagari2, Vivekanand Bongi1, Mythili Ayyagari1, Subramanyam Venkata1
1 Department of Endocrinology, King George Hospital, Visakhapatnam, Telangana, India
2 Department of Medicine, Kamineni Institute of Medical Sciences, Narketpally, Nalgonda, Telangana, India
|Date of Web Publication||1-Jun-2016|
Dr. Srinivas Sidduri
H. no-5-38, Gopalpur, Mandal, Elkathurthy Karimnagar - 505 476, Telangana
Source of Support: None, Conflict of Interest: None
Background: Hypothyroidism affects bile content, bile flow, and functions of the sphincter of Oddi, thereby increases the formation of common bile duct (CBD) stones. The exact prevalence of hypothyroidism in CBD stone patients is not known. Objectives: The aims are: (1) To investigate the prevalence of undiagnosed thyroid dysfunction in CBD stone patients compared with controls, (2) Comparison of lipid parameters in CBD stone patients and healthy controls, (3) Comparison of lipid parameters in CBD stone patients with and without thyroid dysfunction. Materials and Methods: This study recruited 44 CBD stone patients diagnosed with endoscopic retrograde cholangiopancreatography (ERCP) (cases). The control group includes 33 age, sex, and body mass index (BMI) matched healthy people. The control group underwent ultrasonography to exclude any asymptomatic cholelithiasis. Fasting blood samples were taken from all participants for measurements of serum total thyroxine (T4), serum thyroid stimulating hormone (TSH), triglycerides (TG), total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). Results: The mean values of TSH in cases and controls were 3.57 ± 1.7 and 2.58 ± 0.67, respectively (P value 0.0029). Subclinical hypothyroidism (SCH) found in 30% of cases compared with 9.09% of controls (P value < 0.05). In the CBD stone group, the prevalence of SCH was 36% in the patients older than 50 year compared to 22% in the less than 50 year age-group (P > 0.05). The prevalence of SCH was more in females (23%) compared with males (11%) (P > 0.05). There is a trend toward increase in the mean values of TC, LDL, and TG levels in cases compared to controls. There is a non-significant increase in mean HDL values in cases. On subanalysis of lipid parameters in CBD stone patients with and without thyroid dysfunction, there is a trend toward an increase in the mean TC and LDL-C in cases with SCH compared to those without SCH (P > 0.05). Conclusions: SCH was more common in the CBD stone patients compared with controls. SCH was more prevalent in CBD patients older than 50 years of age. Prevalence of SCH in CBD stone patients was more common in females compared to males. Dyslipidemia may be one of the contributing factors for increased CBD stone formation in SCH.
Keywords: Common bile duct stones, dyslipidemia, hypothyroidism, subclinical hypothyroidism
|How to cite this article:|
Sidduri S, Hanmayyagari B, Bongi V, Ayyagari M, Venkata S. Prevalence of hypothyroidism in common bile duct stone patients. Thyroid Res Pract 2016;13:57-62
|How to cite this URL:|
Sidduri S, Hanmayyagari B, Bongi V, Ayyagari M, Venkata S. Prevalence of hypothyroidism in common bile duct stone patients. Thyroid Res Pract [serial online] 2016 [cited 2019 Dec 12];13:57-62. Available from: http://www.thetrp.net/text.asp?2016/13/2/57/159534
| Introduction|| |
The prevalence of common bile duct (CBD) stones in patients with gallbladder stones varies from 8% to 16%., The pathogenesis of gallstones is a complex process involving factors affecting the bile content and bile flow. It has been shown that disturbances in lipid metabolism that occur during hypothyroidism, particularly cholesterol pathway, change the rate of bile excretion and lead to the formation of gallstones.
Studies have been shown that CBD stone patients more significantly often diagnosed to have hypothyroidism and even subclinical hypothyroidism (SCH), compared with gallbladder stone patients or controls., It also suggests that factors other than merely changes in the cholesterol metabolism or bile excretion rate, particularly changes in the function of the Sphincter of Oddi More Details, also may be behind the association between CBD stones and hypothyroidism.
The reduced prorelaxing effect of T4 on the SO in hypothyroidism shown in the experimental investigations , may thus result in delayed emptying of the biliary tract, together with the possible cholesterol load in the bile and decreased hepatocytic excretion rate  may compose an important explanation for the increased association of CBD stones and hypothyroidism.
Ultrasonography actually visualizes bile duct stones in only about 50% of cases, whereas dilatation of the bile duct with a diameter greater than 6 mm is seen in about 75% of cases. Endoscopic retrograde cholangiopancreatography (ERCP) is the standard method for the diagnosis and therapy of bile duct stones, with sensitivity and specificity rates of approximately 95%.
The aim of this study was to investigate the thyroid function, especially the prevalence of previously undiagnosed SCH, in CBD stone patients compared with non-gallstone controls.
| Materials and Methods|| |
This cross-sectional, comparative, case control study was done in department of Endocrinology, King George Hospital, Visakhapatnam during the period of February 2011 to February 2013. Patients with CBD stones attending the outpatient department (OPD) and ward of department of Gastroenterology were screened as cases for the study. Eligible cases were compared to age; gender and body mass index (BMI) matched non-gallstone controls.
Patients who had CBD stones on ultrasonogram, which was confirmed with ERCP were included into the study. Patients who have a history of treated hypothyroidism, presence pregnancy, use of oral contraceptive pills, phenytoin, carbamazepine, metoclopramide, and domperidone, who are critically ill or patients of renal/liver failure, were excluded from the study.
Fasting venous samples were collected from eligible candidates for the estimation of total T4, total T3 and serum thyroid stimulating hormone (TSH), and lipid profile. After separation samples were stored at -22°C till the time of assay, TT3, TT4, and TSH were assayed using chemiluminiscent method (Rosche kit). The normal ranges for TSH and TT4 were 0.3–4.5 µU/ml, respectively. The lower detection limit of these assays was 0.01 µU/ml and the interassay and intra-assay coefficient of variation for all these assays was <10%.
Depending on the values cases and controls divided into the following groups: Euthyroid, SCH (defined as TSH more than 4.5 mIU/ml with normal T3 and T4 levels), overt hypothyroidism (defined as increased TSH and decreased T3, T4 levels).
Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG) was assessed using an enzymatic method and low-density lipoprotein cholesterol (LDL-C) was calculated using Friedewald formula (LDL-C = TC-(HDL-C + TG/5). The interassay and intra-assay coefficient of variation for all these assays was <10%. Dyslipidemia is defined using National Cholesterol Education Program Adult Treatment Panel IIIŠ NCEP ATPIII guidelines, in the presence of any one of the following in a lipid profile done after 12 hr of fasting. TC ≥ 200 mg/dl, HDL-C males <40 mg/dl and females <50 mg/dl, LDL-C ≥ 130 mg/dl, and TG ≥ 150 mg/dl.
The data were presented as mean ± standard devation (SD). The significance between the mean of TSH, TC, HDL-C, LDL-C, and TG in cases and controls were compared using an Unpaired 't' test. The P value of < 0.05 was considered significant.
| Results|| |
Out of 44 cases, 40 cases met the eligibility criteria. These cases were compared with 33 age, gender, and BMI matched controls. The baseline characteristics were depicted in [Table 1]. All the baseline characteristics were similar between cases and controls.
| Discussion|| |
An association between CBD stones and delayed emptying of the biliary tract in experimental and clinical hypothyroidism have been shown earlier, explained at least partly by the lack of the prorelaxing effect of T4 on the sphincter of Oddi contractility.,,
In this study, we investigated the prevalence of previously undiagnosed thyroid function abnormalities in CBD stone patients in our population and found a significant number of patients had thyroid dysfunction.[Table 2] The two study groups were comparable for age, BMI, and gender distribution [Figure 1], [Figrue 2], [Figure 3]. The CBD stone patients were diagnosed to have CBD stones at ERCP procedure. Because there was no suspicion of CBD stones in the control patients, no imaging techniques except for ultrasonography were used to confirm the absence of CBD stones. The most sensitive test for detecting early thyroid failure is an increased serum TSH concentration. In the subclinical form, an increased serum TSH level is accompanied by a normal serum T4 level, and the patient is asymptomatic. In the present study, none of the patients were clinically hypothyroid.
|Figure 2: Gender distribution In our study males are predominant in distribution which accounts to 67% and 57.5% in cases and controls respectively|
Click here to view
|Figure 3: Distribution of BMI BMI distribution in cases and controls. No significant difference in the distribution in both groups. (P > 0.05)|
Click here to view
It was found that in the CBD stone patients, SCH was significantly more common compared with the non-gallstone controls (30% vs. 9.09%; P < 0.05) [Figure 4]. These findings were similar to that shown by Laukkarinen et al. and Hossein Ajdarkosh et al. In the study by Laukkarinen et al., 303 patients with CBD stones were compared with 142 healthy controls of similar age and BMI. They had observed SCH is more common in the CBD stone patients, compared with non-gallstone controls, (10.2% vs. 2.8%: P = 0.026) supporting the hypothesis that hypothyroidism might play a role in the forming of CBD stones. Hossein Ajdarkosh et al. compared 151 CBD stone patients with controls and showed a prevalence of 30.3% in cases compared to 22.5% in the control group. In our study and the study by Hossein Ajdarkosh et al. revealed more number of patients with SCH even in the control group. This indicates probably there is increased prevalence of SCH in general population.
|Figure 4: Comparison of thyroid dysfunction between cases and controls. Subclinical hypothyroidism (TSH > 4.5 mIU/litre) diagnosed in 12 CBD stone patients (30%), compared with three controls (9.09%); P < 0.05). None of the patients had overt hypothyroidism|
Click here to view
The prevalence of thyroid dysfunction was more frequent in older than 50 years of age compared to younger than 50 years (36% vs. 22) [Figure 5] and more in females than males (23% vs. 11) [Figure 6]. In the study by Laukkarinen et al., the prevalence of SCH in women with CBD stone patients older than 60 year was 11.4% compared with 1.8% in the controls (P = 0.032). They also suggested that at least this subgroup of patients might need to be screened for current thyroid dysfunction. But in our present study none of the female patients older than 60 years were found to have thyroid dysfunction. This might be due to small sample size and less number of females compared to males in our study.
|Figure 5: Subclinical hypothyroidism in CBD stone patients in relation to age. In patients older than 50 yr in the CBD stone group, the prevalence of subclinical hypothyroidism was 36% compared to 22% in the less than 50 year age group (P > 0.05)|
Click here to view
|Figure 6: Subclinical hypothyroidism in CBD stone patients in relation to sex. In patients with CBD stones, the prevalence of subclinical hypothyroidism was more in females (23%) compared with males (11%). The difference is statistically not significant (P < 0.05)|
Click here to view
Hypothyroidism is consistently associated with elevations of TC, LDL-C, as well as elevated concentrations of serum triglycerides and C-reactive protein that improves with T4 treatment. Most studies have shown that serum HDL levels are not influenced by thyroid status.
In our present study, we compared the lipid profile between cases and controls [Table 3]. There is a trend toward an increase in the mean values of TC, LDL, and triglyceride levels in cases compared to controls. There is a non-significant increase in mean HDL values in cases. These results were similar to those of Hossein Ajdarkosh et al., in which the mean TC levels in cases were higher than the control group (P = 0.61). Serum hypercholesterolemia in hypothyroidism results in supersaturated bile with cholesterol. A direct consequence of cholesterol supersaturated bile is reduced motility, depressed contractility, and impaired filling  of the gallbladder, giving rise to prolonged stay of bile in the gallbladder. This may contribute to the retention of cholesterol crystals, thereby allowing sufficient time for nucleation and continuous growth into mature gallstones.
On subanalysis of lipid parameters in CBD stone patients with and without thyroid dysfunction [Table 4] and [Figure 7], there is a trend toward an increase in the mean TC and LDL in cases with SCH compared to those without SCH (P > 0.05). This might be due to the expression of cell surface LDL-C receptor levels decreased in fibroblasts, liver, and other tissues. The decrease in LDL-C receptors leads to reduced clearance of LDL-C from the serum. Hypothyroidism may also lead to increased intestinal cholesterol absorption due to thyroid hormone actions on Niemann-Pick C1-like 1protein in the gut. Thyroid hormone induces the hepatic expression of HMG Co-A reductase, which results in increased cholesterol synthesis. Therefore, in overt hypothyroidism, hepatic cholesterol synthesis is decreased. However, the thyroid hormone effects on LDL-C receptor expression and cholesterol absorption outweigh the effects of decreased hepatic cholesterol synthesis, leading to a net accumulation of serum LDL-C in overt hypothyroidism. It is likely that more subtle manifestations of the same alterations that occur in overt hypothyroidism are present in mildly hypothyroid patients.
|Table 4: Comparison of lipid profiles in common bile duct (CBD) stone patients with or without subclinical hypothyroidism|
Click here to view
|Figure 7: Comparison of lipid parameters in CBD stone patients with or without subclinical hypothyroidism Total cholesterol > 200 mg/dl seen in 41% of cases with SCH compared to 32% in without SCH (P > 0.05). HDL < 50 in female and < 40 in male seen in 25% in cases with SCH compared to 14% in without SCH (P > 0.05.) Triglycerides > 150 mg/dl seen in 16.6 % in cases with SCH compare to 14 % in cases without SCH (P > 0.05). LDL > 130 mg/dl seen in 16.6 % in cases with SCH compared to 25 % in cases without SCH (P > 0.05)|
Click here to view
There is no difference of mean values of triglycerides in CBD patients with or without SCH. According to previous studies, triglyceride levels and VLDL may be normal or increased in hypothyroidism. The mean of HDL-C was higher in CBD stone patients with SCH than without SCH (P = 0.01) which was also noted in other population based studies like Cannaris et al. and Bell et al. This could be due to reduced hepatic lipase activity  resulting in decreased metabolism of HDL-C and the reduced Cholesterol Ester Transfer Protein CETP activity  resulting in decreased transfer of triglycerides to HDL-C in exchange for cholesterol ester in SCH. This leads to decreased hydrolysation of HDL-C which results in decreased metabolism of HDL-C, but this hypothesis could not be confirmed as the type of HDL-C was not assessed.
The limitations of the present study were (1) sample size was small, (2) Friedewald formula was used for estimation of LDL-C instead of directly measuring LDL-C. This method was inaccurate especially when TG levels were >400 mg/dl. But none of our patients had such high values. So this limitation might not have altered the results to a greater extent.
In summary, SCH is more common in the CBD stone patients, which supports the previous hypothesis that hypothyroidism might play a role in the formation of CBD stones. Further studies are needed to investigate whether early treatment of subclinical or overt hypothyroidism could prevent the CBD stones in these patients. At least a subgroup of CBD stone patients (older than 50 years of age, females) should be screened for thyroid dysfunction and offered replacement therapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Applemann RM, Priestley JT, Gate RP. Cholelithiasis and choledocholithiasis: Factors that influence relative incidence. Mayo Clin Proc 1964;39:473-9.
Jordan GL Jr. Choledocholithiasis. Curr Probl Surg 1982;19:722-98.
Laukkarinen J, Kiudelis G, Lempinen M, Räty S, Pelli H, Sand J, et al
. Increased prevalence of subclinical hypothyroidism in common bile duct stone patients. J Clin Endocrinol Metab 2007;92:4260-4.
Honore LH. A significant association between symptomatic cholesterol cholelithiasis and treated hypothyroidism in women. J Med 1981;12:199-203.
Inkinen J, Sand J, Nordback I. Association between common bile duct stones and treated hypothyroidism. Hepatogastroenterology 2000;47:919-21.
Inkinen J, Sand J, Arvola P, Porsti I, Nordback I. Direct effect of thyroxine on pig Sphincter of Oddi contractility. Dig Dis Sci 2001;46:182-6.
Laukkarinen J, Sand J, Aittomäki S, Pörsti I, Kööbi P, Kalliovalkama J, et al
. Mechanism of the prorelaxing effect of thyroxine on the sphincter of Oddi. Scand J Gastroenterol 2002;37:667-3.
Andreini, Prigge, Ma C, Gebhard R. Vesicles and mixed micelles in hypothyroid rat bile before and after thyroid hormone treatment: Evidence for a vesicle transport system for biliary cholesterol secretion. J Lipid Res 1994;35:1405-12.
Executive summary of the Third Report of The National Cholesterol Education Program (NCEP). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. (Adult Treatment Panel III). JAMA 2001;285:2486-97.
Laukkarinen J, Sand J, Aittomäki S, Pörsti I, Kööbi P, Kalliovalkama J, et al
. Mechanism of the prorelaxing effect of thyroxine on the sphincter of Oddi. Scand J Gastroenterol 2002;37:667-73.
Laukkarinen J, Koobi P, Kalliovalkama J, Sand J, Mattila J, Turjanmaa V, et al
. Bile flow to duodenum is reduced in hypothyreosis and enhanced in hyperthyreosis. Neurogastroenterol Motil 2002;14:183-8.
Laukkarinen J, Sand J, Saaristo R, Salmi J, Turjanmaa V, Vehkalahti P, et al
. Is bile flow reduced in patients with hypothyroidism? Surgery 2003;133:288-93.
Ajdarkosh H, Khansari MR, Sohrabi MR, Hemasi GR, Shamspour N, Abdolahi N, et al
. Thyroid dysfunction and choleduocholithiasis. Middle East J Dig Dis 2013;5:141-5.
Donovan JM. Physical and metabolic factors in gallstone pathogenesis. Gastroenterol Clin North Am 1999;28:75-97.
Behar L, Lee KY, Thompson WR, Biancani P. Gallbladder contraction in patients with pigment and cholesterol stones. Gastroenterology 1989;97:1479-84.
Gaman C, Bonde Y, Matasconi M, Angelin B, Rudling M. Dramatically increased intestinal absorption of cholesterol following hypophysectomy is normalized by thyroid hormone. Gastroenterology 2008;134:1127-36.
Choi JW, Choi HS. The regulatory effects of thyroid hormone on the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Endocr Res 2000;26:1-21.
O'Brien T, Dinneen SF, O'Brien PC, Palumbo PJ. Hyperlipidemia in patients with primary and secondary hypothyroidism. Mayo Clin Proc 1993;68:860-6.
Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med 2000;160:526-34.
Bell RJ, Rivera-Woll L, Davison SL, Topliss DJ, Donath S, Davis SR. Well-being, health-related quality of life and cardiovascular disease risk profile in women with subclinical thyroid disease a community-based study. Clin Endocrinol (Oxf) 2007;66:548-56.
Brenta G, Berg G, Arias P, Zago V, Schnitman M, Muzzio ML, et al
. Lipoprotein alterations, hepatic lipase activity, and insulin sensitivity in subclinical hypothyroidism: Response to L-T (4) treatment. Thyroid 2007;17:453-60.
Sigal GA, Medeiros-Neto G, Vinagre JC. Lipid metabolism in subclinical hypothyroidism: Plasma kinetics of triglyceride-rich lipoproteins and lipid transfers to high-density lipoprotein before and after levothyroxine treatment. Thyroid Official J Am Thyroid Assoc 2001;21:347-53.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4]